Organ transplantation or the transfer of an organ from one human to another continues to rise throughout the world as the treatment of choice when an organ is irreversibly damaged and organ function is severely impaired. Organ transplantation is not without complications, not only from the transplant surgery itself, but also from the transplant recipient's own immune system and this process, if it happens suddenly, is called acute rejection.
For example, when acute rejection of a kidney transplant occurs, it manifests itself by a sudden deterioration in kidney transplant function, and about 30 percent of the transplant recipients experience an episode of acute rejection. Acute rejection can be associated with about a 20 percent reduction in the one-year survival rate of kidney grafts from a deceased donor, and the projected half-life is about four years shorter in patients who have had an episode of acute rejection compared to patients who have not had an episode of acute rejection.
Sometimes, acute rejection can result from the activation of recipient's T cells and/or B cells; the rejection primarily due to T cells is classified as T cell mediated acute rejection or acute cellular rejection (ACR) and the rejection in which B cells are primarily responsible is classified as antibody mediated acute rejection (AMR). Often times acute rejection of either type can result in the complete loss of transplant function and transplant failure.
In particular, for kidney transplants, an increase in the level of serum creatinine, a clinically used measure of kidney function, is often the first clinical indicator of acute rejection, and is currently the best surrogate marker of acute rejection of either type. However, this biomarker lacks sensitivity and specificity since graft dysfunction can occur due to a non-immunologic causes as well.
For example, two of the commonly used drugs in transplant recipients to prevent rejection, cyclosporine as well as tacrolimus, can cause kidney toxicity, and this complication is not readily identified solely on the basis of blood concentrations of cyclosporine/tacrolimus. In kidney transplant patients, the clinical importance of distinguishing acute rejection from cyclosporine/tacrolimus toxicity cannot be overemphasized since the treatment approaches are diametrically opposite. In one instance, continued administration of cyclosporine/tacrolimus for rejection is critical whereas, in the other instance, a reduction in dosage or discontinuation of cyclosporine/tacrolimus is indicated to prevent further kidney toxicity. Furthermore, deterioration in kidney function is not always available as a clinical clue to diagnose rejection because many of the kidney transplants suffer from acute (reversible) renal failure in the immediate post-transplantation period due to injury from organ procurement and the ex-vivo preservation procedures involved.
Currently, acute rejection is diagnosed by performing the invasive core needle biopsy procedure, which obtains a biopsy of the kidney graft. The histological features in the allograft biopsy is then observed. However, this invasive biopsy procedure is associated with complications such as bleeding, arteriovenous fistula, graft loss, and, in severe cases, even death.
Development of a noninvasive test either to anticipate an episode of acute rejection or to diagnose acute rejection without performing the transplant biopsy procedure is a major and an unmet goal in organ transplantation. The benefit of development of a noninvasive test to anticipate acute rejection is that rejection could be identified prior to organ injury and graft dysfunction and preemptive anti-rejection therapy can be started. Similarly, the benefit of diagnosing rejection with a noninvasive test is that the invasive biopsy procedure that can be associated with complications such as bleeding and even death of the patient could be avoided. Further, it would be beneficial to have a noninvasive test that can anticipate acute transplant rejection as well as serve as surrogates for the biopsy procedure. It would also be beneficial to provide a non-invasive test that provides information regarding the mechanisms responsible for acute rejection, and anti-rejection therapy can be customized to the specific biomarkers of the patient, and therefore, the “one size fits all” approach to treat all transplants the same way can be avoided. Therefore, there is a need for new methods and compositions for detecting acute transplant rejection. Non-invasive tests that predict acute rejection and its timeline would also be very useful.